We propose to analyze the covalent and non-covalent interaction of substrate with proteins using quantum mechanical and molecular mechanical methods. Specifically, we propose to develop a water model including non-additivity to analyze the solvation energy of a number of ionic small molecules of importance in the interaction of thyroxine analogs with prealbumin and the interaction of substrates and inhibitors of triose phosphate isomerase. The goals of the research are: to predict the relative binding free energies of thyroxine analogs to prealbumin and to correctly model the non-catalyzed and enzyme catalyzed isomerization reactions of dihydroxyacetone phosphate. The achievement of these goals should lead to a model which can be useful in the rational design of drugs.